Gut microbiota's causative relationship with peripheral artery disease: a Mendelian randomization study.

Introduction: The relationship between gut microbiota and peripheral artery disease (PAD) remains understudied. While traditional risk factors like smoking and hyperlipidemia are well-understood, our study aims to determine the potential causative association of gut microbiota with PAD using Mendelian Randomization. Methods: Data from the International MiBioGen Consortium and the FinnGen research project were used to study 211 bacterial taxa. Instrumental variables, comprising 2079 SNPs, were selected based on significance levels and linkage disequilibrium. Analyses were conducted utilizing the inverse-variance weighted (IVW) method and other statistical MR techniques to mitigate biases, processed in R (v4.3.1) with the TwosampleMR package. Results: Three bacterial taxa, namely genus Coprococcus2, RuminococcaceaeUCG004, and RuminococcaceaeUCG010, emerged as protective factors against PAD. In contrast, family. FamilyXI and the genus Lachnoclostridium and LachnospiraceaeUCG001 were identified as risk factors. Conclusion: Our findings hint at a causative association between certain gut microbiota and PAD, introducing new avenues for understanding PAD's etiology and developing effective treatments. The observed associations now warrant further validation in varied populations and detailed exploration at finer taxonomic levels.

Mitochondria-Specific Molecular Crosstalk between Ferroptosis and Apoptosis Revealed by In Situ Raman Spectroscopy.

Ferroptosis and apoptosis are two types of regulated cell death that are closely associated with the pathophysiological processes of many diseases. The significance of ferroptosis-apoptosis crosstalk in cell fate determination has been reported, but the underlying molecular mechanisms are poorly understood. Herein mitochondria-mediated molecular crosstalk is explored. Based on a comprehensive spectroscopic investigation and mass spectrometry, cytochrome c-involved Fenton-like reactions and lipid peroxidation are revealed. More importantly, cytochrome c is found to induce ROS-independent and cardiolipin-specific lipid peroxidation depending on its redox state. In situ Raman spectroscopy unveiled that erastin can interrupt membrane permeability, specifically through cardiolipin, facilitating cytochrome c release from the mitochondria. Details of the erastin-cardiolipin interaction are determined using molecular dynamics simulations. This study provides novel insights into how molecular crosstalk occurs around mitochondrial membranes to trigger ferroptosis and apoptosis, with significant implications for the rational design of mitochondria-targeted cell death reducers in cancer therapy.

In Situ Monitoring of Membrane Protein Electron Transfer via Surface-Enhanced Resonance Raman Spectroscopy.

In situ analysis of membrane protein-ligand interactions under physiological conditions is of significance for both fundamental and applied science, but it is still a big challenge due to the limits in sensitivity and selectivity. Here, we demonstrate the potential of surface-enhanced resonance Raman spectroscopy (SERRS) for the investigation of membrane protein-protein interactions. Lipid biolayers are successfully coated on silver nanoparticles through electrostatic interactions, and a highly sensitive and biomimetic membrane platform is obtained in vitro. Self-assembly and immobilization of the reduced cytochrome b5 on the coated membrane are achieved and protein native biological functions are preserved. Owing to resonance effect, the Raman fingerprint of the immobilized cytochrome b5 redox center is selectively enhanced, allowing for in situ and real-time monitoring of the electron transfer process between cytochrome b5 and their partners, cytochrome c and myoglobin. This study provides a sensitive analytical approach for membrane proteins and paves the way for in situ exploration of their structural basis and functions.

Time-course transcriptome analysis of lungs from mice infected with inhaled aerosolized Stenotrophomonas maltophilia.

Background: Stenotrophomonas maltophilia (SMA) has emerged as an important pathogen capable of causing an opportunistic and nosocomial infection. We performed RNA sequencing (RNA-seq) of lung tissues from mice with pulmonary SMA infection over time via aerosolized intratracheal inhalation to investigate transcription profile changes in SMA-infected lungs. Methods: A mouse model of acute lethal SMA pneumonia was established in this study using aerosolized intratracheal inhalation, laying the groundwork for future SMA research. RNA-seq was then used to create a transcriptional profile of the lungs of the model mice at 0, 4, 12, 24, 48, and 72 hours post-infection (hpi). Mfuzz time clustering, weighted gene coexpression network analysis (WGCNA), and Immune Cell Abundance Identifier for mouse (ImmuCellAI-mouse) were used to analyze RNA-seq data. Results: A gradual change in the lung transcriptional profile was observed, which was consistent with the expected disease progression. At 4 hpi, the expression of genes related to the acute phase inflammatory response increased, as predicted abundance of innate immune cells. At this stage, an increased demand for energy was also observed, including an increase in the expression of genes involved in circulation, muscle function and mitochondrial respiratory chain function. The expression of genes associated with endoplasmic reticulum stress (ERS) and autophagy increased at 24 hpi. Unlike the number of natural killer (NK) cells following most bacterial lung infections, the abundance of NK cells decreased following infection with SMA. The expression levels of Cxcl10, Cd14, Gbp5, Cxcr2, Tnip1, Zc3h12a, Egr1, Sell and Gbp2 were high and previously unreported in SMA pneumonia, and they may be important targets for future studies. Conclusions: To our knowledge, this is the first study to investigate the pulmonary transcriptional response to SMA infection. The findings shed light on the molecular mechanisms underlying the pathogenesis of SMA pneumonia, which may aid in the development of therapies to reduce the occurrence of SMA pulmonary infection.

Asymmetric N-Alkylation of 1H-Indoles via Carbene Insertion Reaction.

An intermolecular enantioselective N-alkylation reaction of 1H-indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N-H bond insertion reaction. N-Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both α-aryl and α-alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X-H (X=N, O, S et al.) and C-H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity.

In Situ and Real-Time Monitoring of Mitochondria-Endoplasmic Reticulum Crosstalk in Apoptosis via Surface-Enhanced Resonance Raman Spectroscopy.

The crosstalk between mitochondria and endoplasmic reticula plays a crucial role in apoptotic pathways in which reactive oxygen species (ROS) produced by microsomal monooxygenase (MMO) are believed to accelerate cytochrome c release. Herein, we successfully demonstrate the potential of surface-enhanced resonance Raman spectroscopy (SERRS) for monitoring MMO-derived ROS formation and ROS-mediated cytochrome c release. Silver nanoparticles coated with nickel shells are used as both Raman signal enhancers and electron donors for cytochrome c. SERRS of cytochrome c is found to be sensitive to ROS, allowing for in situ probing of ROS formation with a cell death inducer. Label-free evaluation of ROS-induced apoptosis is achieved by SERRS-based monitoring of cytochrome c release in living cells. This study verifies the capability of SERRS for label-free, in situ, and real-time monitoring of the mitochondria-endoplasmic reticulum crosstalk in apoptosis and provides a novel strategy for the rational design and screening of ROS-inducing drugs for cancer treatment.

Asymmetric Arylation of Diazoesters with Anisoles Enabled by Cooperative Gold and Phosphoric Acid Catalysis.

An enantioselective insertion of a carbene into the Csp2-H bond of anisole derivatives has been accomplished using an achiral gold complex and a chiral phosphoric acid as the catalytic system, providing a novel protocol for the synthesis of chiral α,α-diaryl acetates. Density functional theory calculations reveal the reactivity and the origin of the enantioselectivity of this reaction.

Construction of C-C Axial Chirality via Asymmetric Carbene Insertion into Arene C-H Bonds.

By using diazonaphthoquinones and anilines as key reagents and through a point-to-axis chiral transfer strategy, the atroposelective synthesis via asymmetric C(sp2 )-H bond insertion reaction of arenes has been realized under rhodium catalysis, providing the resulting biaryl atropisomers in moderate to excellent yields with good enantiomeric ratios (up to 99:1). Further elaboration indicates this type of axially biaryl scaffold may have promising potentials in developing novel chiral ligands.

Copper-Catalyzed Tandem Cross-Coupling and Alkynylogous Aldol Reaction: Access to Chiral Exocyclic α-Allenols.

An enantioselective copper-catalyzed tandem cross-coupling/alkynylogous aldol reaction has been developed. The tetrasubstituted allenoates containing both central and axial chirality have been obtained in moderate to good yields and excellent enantio- and diastereoselectivity. Distinct from the previous use of Cu(I) salts, this protocol features the use of copper(II) salts as a catalytic precursor in this asymmetric cross-coupling reaction.

Chemo- and Enantioselective Insertion of Furyl Carbene into the N-H Bond of 2-Pyridones.

Asymmetric carbene insertion reactions represent one of the most important protocols to construct carbon-heteroatom bonds. The use of donor-acceptor diazo compounds bearing an ester group is however a prerequisite for achieving high enantioselectivity. Herein, we report a chemo- and enantioselective formal N-H insertion of 2-pyridones that has been accomplished for the first time with enynones as the donor-donor carbene precursors. DFT calculations indicate an unprecedented enantioselective 1,4-proton transfer from O to C. The rhodium catalyst provides a chiral pocket in which the steric repulsion and the π-π interaction of the propeller ligand play a critical role in determining the selectivities.

An Innovative Customized Stent Graft Manufacture System Assisted by Three-Dimensional Printing Technology.

BACKGROUND: Commercially available thoracic aortic stent grafts rarely match the geometric characteristics of the aorta perfectly, which can lead to complications. Customization maybe a solution for this problem, but the delay inherent in the current manufacturing process makes it unable to meet the urgent requirement of acute aortic events. We established and optimized a rapid design and manufacture system for a customized aortic stent graft assisted by 3-dimensional (3D) printing technology. We also evaluated the preliminary feasibility and capability of this customized stent graft. METHODS: Seven essential production steps comprised the rapid design and manufacture process for the customized stent graft system assisted by 3D printing technology. Optimization of the manufacture process was refined over time in 3 stages. Bench test and in vivo experiments were used to verify the feasibility of this system and evaluate the preliminary usability of the customized stent graft. RESULTS: After optimization, the theoretical production time of the customized stent graft was reduced to approximately 12 hours. Bench test showed radial forces against the aorta wall were better distributed in the customized stent graft than in the control stent graft. In vivo experimental results showed that the customized stent graft system worked effectively. CONCLUSIONS: It was feasible to rapidly design and manufacture a customized aortic stent graft assisted by 3D printing technology, which demonstrated better geometric compliance and physical characters in the bench test and in in vivo experimentation. The manufacturing process could be accelerated to approximately 12 hours, which might be optimized further to meet urgent clinic requirements.

Site-Selective Functionalization of 7-Azaindoles via Carbene Transfer and Isolation of N-Aromatic Zwitterions.

The first systematic study on metal-carbene transfer reaction of 7-azaindoles has been conducted, and the unprecedented dearomative N7-alkylation reaction has been accomplished via ruthenium catalysis. Importantly, through a sequential dearomatization-aromatization process, an isolable, and new class of azaindole-based N-aromatic zwitterions has been discovered from the reaction of 7-azaindoles and diazoesters.

Dearomative Migratory Rearrangement of 2-Oxypyridines Enabled by α-Imino Rhodium Carbene.

The unprecedented dearomative migratory rearrangement reactions of 2-oxypyridines with N-sulfonyl-1,2,3-triazoles have been developed under rhodium catalysis, providing a reliable and efficient protocol for accessing N-substituted 2-pyridones. These two distinct rearrangements feature the controllable 1,4-migration of a carbonate group from O-to-C as well as the O-to-N 1,6-migration of an acyl group via α-imino rhodium carbene transfer. Moreover, the reaction of pyridotriazoles with 2-oxypyridines delivers the 1,4-migration products in high efficiency.

Gold-Catalyzed Intermolecular Formal [4 + 2 + 2]-Cycloaddition of Anthranils with Allenamides.

The construction of eight-membered rings is a challenging issue due to unfavorable transannular strain and entropic barriers. We report herein a gold-catalyzed formal [4 + 2 + 2] cycloaddition reaction of anthranils with allenamides to deliver oxa-bridged eight-membered heterocycles in accepted yields with unique E/Z configuration. Moreover, the asymmetric [4 + 2 + 2] cycloaddition by using chiral phosphoramidite gold catalyst has also been conducted.

Copper-Catalyzed Amino-oxymethylation of Ynamides with N,O-Acetals.

A copper-catalyzed 1,2-difunctionalization of ynamides has been developed by using readily available N,O-acetals as the bifunctional reagents. Importantly, contrary to the initially expected 1,2-oxy-aminomethylation reaction, an unprecedented 1,2-amino-oxymethylation has been observed. This reaction is atom-economical and tolerates a broad substrate scope, affording the difunctionalization products in good yield with unique Z configuration.

Catalyst-Controlled Selective Alkylation/Cyclopropanation of Indoles with Vinyl Diazoesters.

A catalyst-controlled selective functionalization of indoles with vinyl diazoacetates has been developed. The use of gold catalysts exclusively leads to C3-alkylation products, whereas the highly diastereoselective cyclopropanation reaction is dominant for silver catalysis. Importantly, the gold and silver vinylcarbenes exhibit highly carbenic rather than vinylogous reactivity in these transformations.

B(C6F5)3-Catalyzed formal (4+1)-annulation of ortho-quinone methides with diazoacetates: access to 2,3-dihydrobenzofurans.

A novel (4+1)-cycloaddition reaction of alkyne-tethered ortho-quinone methides with diazoacetates has been well established by using B(C6F5)3 as the catalyst, providing 2,3-dihydrobenzofuran derivatives containing a newly formed quaternary carbon center in good yields and diastereoselectivities (up to >19 : 1 dr).

Rhodium-Catalyzed C═N Bond Formation through a Rebound Hydrolysis Mechanism and Application in ß-Lactam Synthesis.

A rhodium-catalyzed reaction of N-hydroxyanilines with diazo compounds to produce α-imino esters was developed. Distinct from the commonly accepted 1,2-H transfer for normal X-H insertion reactions, density functional theory calculations indicate that this transformation proceeds via a novel rebound hydrolysis mechanism. Furthermore, a three-component reaction was explored to synthesize highly functionalized ß-lactams in good yields and diastereoselectivities.

Access to N-Substituted 2-Pyridones by Catalytic Intermolecular Dearomatization and 1,4-Acyl Transfer.

A novel rhodium-catalyzed dearomatization of O-substituted pyridines to access N-substituted 2-pyridones has been developed. A computational study suggests a mechanism involving the formation of a pyridinium ylide followed by an unprecedented 1,4-acyl migratory rearrangement from O to C. Furthermore, the chiral dirhodium complexes serve as the catalyst for the asymmetric transformation with excellent enantioselective control. DFT calculations indicate the chirality is transferred from axial chirality to the central stereogenic centre. The stronger π-π interaction and CH-π interaction account for the high enantioselectivity.

Rhodium-Catalyzed Regioselective N2 -Alkylation of Benzotriazoles with Diazo Compounds/Enynones via a Nonclassical Pathway.

A novel rhodium-catalyzed highly selective N2 -alkylation of benzotriazoles with diazo compounds/enynones is achieved, providing N2 -alkylated benzotriazoles in good to excellent yields and with excellent N2 selectivities. Importantly, different to traditional carbene insertion into X-H (X=N, O etc) bonds, DFT calculations disclose that this selective N2 -alkylation probably proceeds through a formal 1,3- rather than 1,2-H shift to give the final products.